Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries

Wareing, Mark; Myers, Jenny; O’Hara, Maureen; Kenny, Louise C.; Warren, Averil Y.; Taggart, Michael J.; Skillern, Laurence; Ian, Machin; Baker, Philip N.

doi:10.1016/j.ajog.2003.12.024

Cited by 56 publications

(30 citation statements)

References 36 publications

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“…They demonstrated that SC was metabolised more rapidly in pregnancy to its less efficacious form, desmethyl-sildenafil [23] . Some authors [10,23] suggest that the altered plasma volume and pH in pregnancy necessitates higher doses of SC to reach a therapeutic plasma concentration. In line with this, a subsequent double-blind RCT by Trapani et al [24] utilised a higher SC dose regimen of 50 mg 8-hourly amongst participants with PET.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes

Dunn

Greer²,

Flenady³

et al. 2016

Fetal Diagn Ther

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Introduction: This systematic review evaluates maternal tolerance and obstetric and perinatal outcomes following sildenafil citrate (SC) use in human pregnancy. Data Sources: Scopus, PubMed, Cochrane Library, Web of Science, Embase, and Google Scholar were searched. Relevant full-text studies including case series and reports in English were included. Publications were excluded if the pregnancy was terminated or if SC was used only at conception. Results: Sixteen studies were included (n = 165). Indications for use and outcomes were variably reported. Maternal outcomes reported were headache (45.8%, 49/107), visual disturbances (17.3%, 14/81), dyspepsia/epigastric pain (15.8%, 15/95), and hypotension (0%, 0/39). There were more caesarean (83.3%, 55/66) than vaginal deliveries (16.7%, 11/66) and postpartum haemorrhage occurred in 3.9% (3/76) of women exposed to SC. Neonatal outcomes including nursery admission (67.3%, 35/52), Apgar scores <7 at 5 min (7.1%, 4/56), and cord arterial pH <7.1 (0%, 0/17) were reported. Stillbirths (4.3%, 3/69) and neonatal deaths (3.9%, 5/129) were comparable to SC-naïve groups. There were no congenital malformations (0%, 0/35). Conclusions: Despite limited data, overall there does not appear to be any severe adverse maternal side effects nor any increase in the rate of stillbirths, neonatal deaths, or congenital anomalies attributed to SC.

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Section: Discussionmentioning

confidence: 99%

Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes

Dunn

Greer²,

Flenady³

et al. 2016

Fetal Diagn Ther

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“…16 In addition, impaired endotheliumdependent vasodilation of myometrial arteries taken from women with PE and FGR is improved, ex vivo, after PDE5 inhibition. 18,19 There is, therefore, evidence that vasodilation of the uterine circulation is impaired in PE and FGR, which may be attributed in part to reduced NO-mediated vasodilation. In addition, these studies suggest that PDE5 inhibition by Sildenafil may be able to improve uterine artery vasodilation, thus mediating improved uteroplacental perfusion and increased fetal growth.…”

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confidence: 99%

Sildenafil Citrate Rescues Fetal Growth in the Catechol- O -Methyl Transferase Knockout Mouse Model

et al. 2012

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Abstract-Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT Ϫ/Ϫ ). COMT Ϫ/Ϫ and C57BL/6J mice were treated (0.2 mg/mL in drinking water, nϭ6 -12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT Ϫ/Ϫ mice; this was normalized after treatment with Sildenafil. COMT Ϫ/Ϫ mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT Ϫ/Ϫ mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction. (Hypertension. 2012;59:1021-1028.) • Online Data Supplement Key Words: preeclampsia Ⅲ fetal growth restriction Ⅲ mice Ⅲ uterine artery Ⅲ umbilical artery P reeclampsia (PE) and fetal growth restriction (FGR) are pregnancy-specific disorders that complicate Յ10% of all pregnancies.1 Together they are responsible for the majority of maternal and fetal morbidity and mortality associated with complicated pregnancies.2,3 PE, characterized by the onset of hypertension and proteinuria during pregnancy, is a leading cause of maternal mortality. 4,5 It is also associated with an increased risk of stillbirth, sudden infant death, and FGR.1 FGR, which is defined as a fetus that fails to reach its genetic growth potential, may be observed in the presence or absence of PE. It is associated with a greatly increased risk of perinatal mortality and stillbirth 6 ; smaller size at birth is also associated with longer-term health consequences, such as an increased risk of developing cardiovascular disease and/or metabolic syndrome later in life.7 There are currently only limited treatment options available for PE and none for FGR; an effective therapeutic strategy would have major clinical significance.The etiology of PE and FGR is complex and as yet poorly understood; common to both conditions, however, is an increase in uterine artery resistance.8 This leads to reduced uteroplacental perfusion 9,10 ;...

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“…Therefore, treatment using NO and PDE5 inhibitors might oppose endothelial vasoconstriction, suggesting that these agents offer a potential therapeutic strategy for the management of preeclampsia [66]. Preclinical studies by Wareing et al [67] showed that a PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia. However, another report demonstrated that use of PDE5 inhibitors does not alter endothelial-dependent relaxation [68].…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic-Induced Hypertension: The Molecular Basis of Signaling Network

Nagai¹,

Sado²,

Naruse³

et al. 2012

Gynecol Obstet Invest

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Problem: Preeclampsia, a pregnancy-related hypertensive disorder, is one of the leading causes of fetal and maternal death globally. Angiogenic factors including vascular endothelial growth factor (VEGF) are involved in the formation of new blood vessels required for placental development and function. The hallmark of preeclampsia is similar to the toxicities related to antiangiogenesis therapy. VEGF inhibitors or antagonists promote vasoconstriction, hypertension and proteinuria. VEGF plays a role in attenuating hypertension and improving kidney damage in an animal model; however, the mechanisms underlying this effect remain poorly defined. The aim of this paper is to summarize recent advances in VEGF-mediated signaling and the target molecules, and provide new insights into treatment strategies for preeclampsia. Method of Study: This article reviews the English-language literature for pathogenesis of preeclampsia based on VEGF signaling and hypertension. Results: VEGF activates downstream signaling molecules, including Ca²⁺/CAMKK, Rac1/NOX, ROS/ERK, Ezrin/Calpain/PI3K/Akt, PLCγ/PKC and Src/HSP90. Among these signalings, important pathways for receptor-triggered intracellular signaling are (1) the PI3K/Akt-dependent, (2) the PLCγ-dependent and (3) the ERK/Egr-1-dependent pathway. VEGF is closely involved in receptor-activated signaling events, leading to eNOS-dependent NO synthesis and eNOS-independent endothelial cell proliferation, respectively, and thus modulates vasoactive function and angiogenic response. Conclusion: This review highlights the potential role of NO in vasodilation, while stress-related ERK activation might act to strengthen angiogenesis, migration and proliferation. We discuss the similarity between preeclampsia and VEGF-targeted therapy-induced hypertension.

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Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries

Cited by 56 publications

References 36 publications

Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes

Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes

Sildenafil Citrate Rescues Fetal Growth in the Catechol- O -Methyl Transferase Knockout Mouse Model

Antiangiogenic-Induced Hypertension: The Molecular Basis of Signaling Network

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